3-alkanol derivatives of 4h(1)benzopyrano(3,4-d)isoxazoles

ABSTRACT

THE COMPOUNDS ARE DERIVATIVES OF 3-ALKANOL-4-H(1) BENZOPYRANO (3,4-D) ISOXAZOLES USEFUL IN THE PREPARATION OF WOOD PRESERVATIVES, MOTHPROOFING AGENTS, PICKLING INHIBITORS AND PHARMACEUTICAL AGENTS, REPRESENTATIVE OF THE COMPOUNDS DISCLOSED IN 4H(1) BENZOPYRANO (3,4 - D) ISOXAZOL-3-METHANOL.

United States Patent 3,707,476 3-ALKANOL DERIVATIVES 0F 4H[1]BENZO-PYRANO[3,4-d]ISOXAZOLES Jules Freedman, Thiensville, Wis., assignor toColgate- Palmolive Company, New York, N.Y. N0 Drawing.Continuation-impart of application Ser. No. 670,775, Sept. 26, 1970.This application Oct. 30, 1970,

Ser. No. 85,799

Int. Cl. C07d 85/22 US. Cl. 260-307 H Claims ABSTRACT OF THE DISCLOSUREThe compounds are derivatives of 3-alkano1-4H[1]benzopyrano[3,4-d]isoxazoles useful in the preparation of woodpreservatives, mothproofing agents, pickling inhibitors andpharmaceutical agents. Representative of the compounds disclosed is4H[l]benzopyrano[3,4 d] isoxazole-B-methano-l.

RELATED CASE This application is a continuation-in-part of copendingapplication Ser. No. 670,775 filed September 26, 1970, now US. Pat. No.3,553,229.

DETAILED DESCRIPTION The novel compounds of the present invention havethe following formula in which X and Y are the same or different membersselected from hydrogen, halo such as chloro, bromo or fiuoro, hydroxy,lower alkyl of l to 4 carbon atoms, nitro, methylenedioxy, lower alkoxysuch as methoxy, ethoxy or propoxy and trifluoromethyl, n is l to 4, Ris hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl or a nuclearsubstituted phenyl such as o-chlorophenyl and pmethoxyphenyl, R ishydrogen, an acyl such as acetyl, trifiuoroacetyl, propionyl, butyryland benzoyl or i -C-Arn in which Am is alkyl contains 3 to 7 carbonatoms such as cyclohexylmethyl and cyclopentyl-ethyl, an aryl,particularly phenyl, a nuclear substituted phenyl such as a halophenylor a lower alkoxyphenyl, for example, p-chlorophenyl or pmethoxyphenyland a heterocyclic group such as pyridyl, piperidyl, furyl, thienyl,pyrryl and pyrrolidyl,

(b) Groups in which R and R 'are joined together to form amino groups inwhich the nitrogen is part of a cyclic group such as morpholino,pyrrolidino, piperidino, 4-lower alkyl-l-piperazino such as4-methyl-1-piperazino, N-phenyl-lower alkyl piperazino orN-hydroxy-lower alkyl piperazino and (c) A cyclic amine group bondedthrough a nuclear carbon to the alkylene chain, including such groups asN- lower alkyl- 3 or 4-piperidyls such as N-methyl- 3-piperidyl,N-ethyl-4-piperidyl and N-isopropyl-S-piperidyl, N-(di-lower alkylamino-lower alkyl)-3 or 4-piperidyls such asN-(beta-climethylaminopropyl)-4-piperidyl and N (betadiethylarninoethyl)-3-piperidy1, N-phenyllower alkyl-3 or 4-piperidy1ssuch as N-benzyl-Ii-piperidyl, N-phenylethyl-4-piperidyl andN-phenylpropyl-3-piperidyl, 3-piperidyl and 4-piperidyl, 3-pyrrolidyl,N-lower alkyl-3-pyrrolidyls such as N-ethyl-3-pyrrolidyl, N-phenylloweralkyl 3 pyrrolidyls such as N-phenylethyl-S- pyrrolidyl.

The compounds of the present invention may be conveniently preparedemploying as the basic starting material a 4-chromanone of the formula 0X II 0 R It in which R, X and Y are as previously defined.

The unsubstituted 4-chromanone is a known compound and the substitutedcompounds may be prepared as described in the literature [(3. D. Hurd,et al., J. Am. Chem. Soc., 76, 5065 (1954) and S. Wawzonek, et al., J.Am. Chem. Som., 76, 1080 (1954)].

Representative of the 4-chromanones which may be employed in thedescribed process are 4-chromanone, 6-methoxy-4-chromanone,6-bromo-4-chromanone, 8-methyl-4-chromanone,6-trifiuoromethyl-4-chromanone, 2,2-dimethyl-4-chromanone,6-chloro-4-chromanone, 2-phenyl-4-chromanone, 6-methyl-4-chromanone,6,7-methyleneclioxy-4-chromanone, and 6-chloro-2-phenyl-4-chromanone.

In the preferred method of preparation of the novel compounds, a4-chromanone is treated with a lower alkyl oxalate such as ethyloxalate, in the presence of a suitable base such as sodium amide, sodiummethoXylate or sodium hydride in an anhydrous reaction medium, such astoluene or benzene, to form a lower alkyl 4-oxochroman-3-glyoxylate. Thering closure is then effected by treating the glyoxylate withhydroxylarnine-hydrochloride in ethanol under refiux conditions thusforming the lower alkyl 4H[ l]benzopyrano[3,4 d]isoxazole-3-carboxylate.

'2 a The described process may be illustrated as follows:

0 Y H 0 Y 1 0 o C2115 g cooclrn R --OC1H5 R Y \O R Y O R n III O--N X o0 0 can wherein R, X and Y are as previously defined and do not partakein or interfere with the reaction.

Representative of the compounds which may be prepared by the aboveprocesses are Ethyl 4-oxochroman-3-glyoxylate,

Ethyl 4H[ 1] benzopyrano[3,4-d] isoxazole-B-carboxylate,

Methyl 4H[1]benzopyrano[3,4-d]isoxazole-3-carboxylate,

Ethyl 6-chloro-4-0Xochroman-3-glyoxylate,

Ethyl 8-chloro-4-oxochroman-3-glyoxylate,

Ethyl 6-chloro-4H[ 1]benzopyrano 3,4-d] isoxazole-3- carborylate,

Ethyl 8-chloro-41H[ l benzopyrano [3 ,4-d] isoXazole-3-carboxylate, and

Methyl 8-methoxy-4H[1]benzopyrano[3,4-d]isoxazole-3- carboxylate.

The lower alkyl 4H[1]benzopyrano[3,4-d]isoxazole3- carboxylates may thenbe treated with a suitable chemical reducing agent, such as lithiumaluminum hydride or phenyl lithium. When they are employed, the reactionis conveniently elfected by intimately combining the reactants in aninert organic solvent such as anhydrous ether, dioxane ortetrahydrofuran. After the reaction is terminated, the desired alcoholis recovered by conventional techniques.

The described process may be illustrated as follows:

ON N

iAlH X k -o o 0 can 4 X -ornon 0 0 Y R Y R in which R, X and Y are aspreviously defined and represent groups that do not interfere with orpartake in the reaction.

Representative of the alcohols which may be prepared by the aboveprocess are the following:

4H[1]benzopyrano[3,4-d]isoxazole-3 -methanol, 8-chloro-4-H 1]benzopyrano [3 ,4-d] isoxazole-3-methanol, 6-methoxy-4H[ l]benzopyrano[3 ,4-d] isoxazole-3- methanol, and6-chloro-4H[1]benzopyrano[3,4-d]isoxazole-3-methanol,

The alcohols in which n is greater than 1 may be conveniently preparedby treating an alcohol in which n is 1 with tosyl chloride to form thecorresponding tosylate. The tosylate may then be treated with sodiumcyanide to form the corresponding nitrile which upon hydrolysis yieldsthe corresponding acid which in turn may be reduced to form the desiredalcohol. The process, if desired, may be repeated to form the higheralcohols.

The above described alcohols serve as convenient starting materials forthe preparation of the esters and carbamates. The esters may be preparedby treating the 4 alcohol with an acylating agent such as acyl halide oracid anhydride.

The process may be illustrated as follows:

in which R is acyl and R, X and Y are as previously defined andrepresent groups which do not partake in or interfere with the reaction.

Representative of the compounds which may be prepared by the describedprocess are the following:

4H[1]benzopyrano[3,4-d]isoxazole-3-methanol acetate,

4H[ 1 benzopyrano [3 ,4-d1isoxazole-3-methanol trifluoroacetate,

8-chloro-4H[ IJbenzopyrano [3 ,4-d] isoxaZole-3,4,5, trimethoxybenzoate, and

4-methyl-7-methoXy-4H[1Jbenzopyrano[3,4-d]isoxazole- 3-nicotinate.

lAmH

ON X Uwmnoocmn I R Y O R in which R, X and Y are as previously definedand represent groups which do not interfere with or partake in thereaction.

Representative of the amines that can be employed in the above reactionare the following:

Ethanolamine, Methylamine, Isopropylamine, Benzylamine, Cyclohexylamine,Pyridine, and 4-methylpiperazine Representative of the compounds whichmay be prepared by the described processes are the following:

Acid addition salts of the compounds of the present invention capable offorming such salts may be conveniently produced by contacting thecompounds with a suitable acid such as formic acid, citric acid, maleicacid, sulfuric acid, hydrochloric acid, succinic acid, tartaric acid,benzoic acid or fumaric acid.

Quaternary ammonium salts may be formed by contacting the compoundscapable of forming such salts with a suitable alkylating agent such asdimethyl sulfate, or an alkyl halide such as methyl chloride, methyliodide or ethyl bromide.

The thiocyanic acid addition salts of the carbamates i of thisinvention, when condensed with formaldehyde, form resinous materialsuseful as pickling inhibitors according to US Pats. 2,425,320 and2,606,155. The compounds also form fiuosilicic acid addition salts whichare useful as moth proofing or wood preserving agents according to US.Pats. 1,915,334 and 2,075,359.

The compounds also form salts with penicillins. These salts havesolubility characteristics which cause them to be useful in thepurification and isolation of penicillins, particularly benzylpenicillin.

The novel compounds of the present invention and their pharmaceuticallyacceptable salts also have utility as muscle relaxants andantidepressant agents. In addition, these compounds are useful asintermediates in the preparation of more complex pharmaceuticalcompounds.

In mouse behavioral studies the compounds 4H[1]benzopyrano[3,4-d]isoxazole-3-methanol carbamate,

8-chloro-4H[1]benzopyrano[3,4-d]isoxazolyl-3-methyl carbarnate,

8-chloro-4H[ 1]benzopyrano[3,4-d]isoXazolyl-3-methyl cyclohexylcarbamateand 8-chloro-4H[1]benzopyrano[3,4-d]isoxazolyl-3-methyl benzyl carbamatewere found in doses of approximately 100 mg./kg. to stimulate touchresponse irritability, vocalization and startle response indicatingcentral nervous system stimulation. The behavioral study was conductedessentially in accordance with the procedure outlined by Irwin in Animaland Clinical Pharmacologic Techniques in Drug Evaluation, Year BookMedical Publishers, Inc., Chicago, Ill. (1964). The approximate LDvalues obtained intraperitoneally in the behavioral studies were allfound to be in excess of 200 mg./kg.

When intended for pharmaceutical use, the compounds are preferablycombined with one or more suitable pharmaceutical diluents and additivesand formed into unit dosage forms for oral or parenteral administrationsuch as tablets, capsules and solutions.

A mixture of 74 g. (0.5 mole) of 4-chromanone and 146 g. (1.0 mole) ofethyl oxalate in 375 ml. of anhydrous toluene is added dropwise over1.25 hours to a suspension of sodium hydride (from 54.4 g. of a 53.3%oil-hydride mixture) in 1 liter of anhydrous toluene under an atomsphereof nitrogen. After stirring at room temperature overnight the reactionmixture is added to 1 kg. of ice and stirred 1 hour. The aqueous layeris separated and the organic phase extracted with five 250 ml. portionof H 0. Acidification of the combined extracts with 75 ml. ofconcentrated hydrochloric acid gives a precipitate of 115.6 g. of abright yellow solid. Recrystallizaiton from 200 ml. of ethanol yieldsethyl 4-oxochroman-3-glyoxylate, M.P. 72-79".

Analysis.Calcd. for C H O (percent): C, 62.90; H, 4.87. Found (percent):C, 62.68; H, 5.03.

EXAMPLE 2 Ethyl 4H l ]benzopyrano 3,4-d] isoxazoie-3-carboxylate Amixture of 99.2 g. (0.4 mole) of ethyl 4-oxochroman- 3-glyoxylate, 29.6g. (0.425 mole) of hydroxylaminehydrochloride and 800 ml. of ethanol isrefluxed for 18 hours, 200 ml. of solvent distilled and the residuecooled to give 83.9 g. of the isoxazole, M.P. 8892. Recrystallizationfrom cyclohexane provides the pure ester, ethyl 4H[1]benzopyrano[3,4-d]isoxazole-3-carboxylate, M.P. 9092.

AnaIysis.--Calcd. for C H NO (percent): C, 63.63; H, 4.53; N, 5.71.Found (percent): C, 63.92; H, 4.67; N, 5.56.

EXAMPLE 3 4H[1]benzopyrano[3,4-d]isoxazole-3-methanol A solution of 14.9g. (0.061 mole) of ethyl 4H[l]benzopyrano[3,4-d]isoxazole-3-carboxylatein a mixture of 25 ml. of dry ether and 25 ml. of benzene is added to asuspension of 1.9 g. (0.05 mole) of LiAlH, in 250 ml. of dry ether whilecooling in an ice bath. After stirring 6 hours at room temperature, themixture is cooled in ice, treated with ml. of 3 N HCl and stirredovernight at room temperature. The ether layer is separated, dried overCaCl and the solvent removed. Recrystallization of the solid residuefrom carbon tetrachloride-cyclohexane gives4H[1]benzopyrano[3,4-d]isoxazole 3 methanol, M.P. 107-108.5.

AnaIysis.--Calcd. for C H NO (percent): C, 65.02; H, 4.47; N, 6.89.Found (percent): C, 65.31; H, 4.51; N, 7.21.

7 EXAMPLE 4 4H[1]benzopyrano[3,4-d]isoxazole 3 methanol carbamate and4H[l]benzopyrano[3,4-d]isoxazole-3-methanol trifluoroacetate A mixtureof 4.06 g. (0.02 mole) of 4H[1]benz0pyrano [3,4-d1isoxazole 3 methanol,2.60 g. (0.04 mole) of NaCNO and ml. of CH CI is magnetically stirredwhile 3.2 ml. (0.043 mole) of trifluoroacetic acid is added dropwise. Aheavy precipitate forms after addition of 1.0 ml. of trifiuoro aceticacid and an additional 30 ml. of CHzClz is required to enable stirring.After addition of the remainder of the acid, the heavy precipitategradually disappears leaving a small amount of a granular solid. After20 minutes, a heavy precipitate again forms but does not subsequentlydissolve. After standing overnight, the precipitate is filtered andwashed well with water. Recrystallization from isopropanol gives thedesired product, MJP'. 185- 188. Recrystallization from 100 ml. ofisopropanol gives 4H [1]benzopyrano[3,4-d]isoxazole 3 methanolcarbamate, M.P. 188-189".

Analysis.Calcd. for C H N O (percent): C, 58.53; H, 4.10; N, 11.38.Found (percent): C, 58.83; H, 4.09; N, 11.18.

Evaporation of the above methylene chloride filtrate leaves a solidresidue which is treated with ml. of hot cyclohexane to give 0.7 g. ofcrude urethane, M.P. 137- 170 as the insoluble portion. Evaporation ofthe cyclohexane yields the crude trifiuoroacetate, M.P. 49-64. Tworecrystallizations from small amounts of petroleum ether gives ananalytical sample of 4H[1]-benzopyrano[3,4-d] isoxazole-3-methanoltrifluoroacetate, M.P. 65.5-66.5".

Analysis.Calcd. for C H F NO (percent): C, 52.18; H, 2.70; F, 19.05; N,4.68. Found (percent): C, 51.79; H, 2.90; F, 19.77; H, 4.53.

EXAMPLE 5 8-chloro-4H[1]benzopyrano[3 ,4-d] isoxazolyl-3 -methylchloroformate A stirred mixture of 10.0 g. (0.042 M) of 8-chloro-4H-[1]benzopyrano[3,4d]isoxazole 3 methanol, 5.08 g. (0.042 M) ofdimethylaniline and 400 ml. of dry benzene at 5 is treated with 50 g. of10% phosgene in benzene after stirring at room temperature overnight,the mixture is washed with water, 1% HCl and water and dried overcalcium chloride.

EXAMPLE 6 8-chloro-4H 1 benzopyrano [3 ,4-d] isoxazolyl'3-methyl Ycarbamate A solution of the above chloroformate (from 5.0 g., 0.021 M ofalcohol) in benzene is treated with 2 equivalents of anhydrous ammonia.After stirring overnight the precipitate is collected, washed well withwater and recrystallized from acetonitrile, M.P. 236238.

Analysis.--Calcd. for C H ClN O (percent): C, 51.34; H, 3.24; Cl, 12.64;N, 9.98. Found (percent): C, 51.58; H, 3.24; Cl, 12.39; N, 9.90.

EXAMPLE 7 8-chloro-4H 1]benzopyrano [3,4-d] isoxazoly1-3-methyl-2-hydroxylethylcarb amate A solution of the chloroformate (from 5.0 g.,0.021 M of alcohol) in benzene is treated with 2.56 g. (0.042 M) ofethanolamine and the mixture stirred for 16 hours at room temperature.Addition of dilute HCl leaves a solid material insoluble in both phases.Filtration and recrystallization from methanol gives the8-chloro-4H[l]benzopyrano[3,4-d]isoxazolyl-3-methyl-2hydroxyethylcarbamate, M.P. 143145.

Analysis.-Calcd. for C H ClN- O (percent): C, 51.79; H, 4.03; Cl, 10.92;N, 8.63. Found (percent): C, 52.01; H, 4.23; CI, 10.90; N, 8.65.

In a similar manner the following compounds may be prepared:

(a) 8-chloro-4H[1]benzopyrano[3,4 d]isoxazolyl 3- methylmethylcarbamate, M.P. 149-151 from ethanol.

Analysis.Calcd. for C H CIN O (percent): C, 52.99; H, 3.76; Cl, 12.03.Found (percent): C, 53.13; N, 3.99; CI, 11.92.

(b) 8 chloro-4H[1]benzopyrano[3,4-d]isoxazolyl-3- methylisopropylcarbamate, M.P. 137138 from ethanol.

Analysis.-Calcd. for C H ClN O (percent): C, 55.82; H, 4.68; Cl, 10.99.Found (percent): C, 55.64; H, 4.38; Cl, 10.75; N, 8.57.

(c) 8 chloro 4H[1]l5enzopyrano[3,4-d]isoxazolyl-3- methylbenzylcarbamate, M.P. 141142 from ethanol.

Analysis.--Calcd. for C H ClN O (percent): C, 61.54; H, 4.08; N, 7.55.Found (percent): C, 61.72; H, 3.89; N, 7.78.

(d) 8 ch'loro 4H[1Jbenzopyrano[3,4-d]isoxazolyl-3- methylcyclohexylcarbamate, M.P. 190-19l from acetonitrile.

Analysis.Calcd. for C H C1N O (percent): C, 59.58; H, 5.28; Cl, 9.77; N,7.72. Found (percent): C, 59.76; H, 5.37; CI, 9.50; N, 7.69.

(e) 8 chloro 4H[1]benzopyrano[3,4-d]isoxazolyl-3-methyl-3-pyridylcarbamate, M.P. 188-189 from methanol.

Analysis.-Calcd. for C H ClN O (percent): C, 57.06; H, 3.38; Cl, 9.91;N, 11.75. Found (percent): C, 57.03; H, 3.49; CI, 9.70; N, 11.59.

(f) 8 chloro 4H[1]benzopyrano[3,4-d]isoxazolyl-3- methyl4-methylpiperazine-l-carboxylate hydrochloride, 253255 from water.

Analysis.Calcd. for C H Cl N O (percent): C, 51.00; H, 4.79; C1, 17.72;N, 10.50. Found (percent): C, 51.14; H, 4.96; Cl, 17.61; N, 10.42.

EXAMPLE 8 8-chloro-4H[ 1]benzopyrano [3 ,4-d] isoxazolyl-3- methylphenylcarbamate A mixture of 5.0 g. (0.021 M) of8-chloro-4H[1]benzopyrano[3,4-d]isoxazole-3-methanol, 2.8 g. (0.023 M)of phenylisocyanate and m1. of anhydrous benzene is refluxed overnight.Water (50 ml.) is added whereupon solids insoluble in both phases form.The solids are filtered and recrystallized from acetonitrile to yield8-ch1oro- 4H[1]benzopyrano[3,4-dlisoxazolyl 3 methyl phenylcarbamate,M.P. 189190 C.

Analysis.Calcd. for C H C1N O (percent): C, 60.58; H, 3.67; CI, 9.94; N,7.85. Found (percent): C, 60.58; H, 3.77; Cl, 9.75; N, 8.29.

EXAMPLE 9 8-chloro-4H 1 benzopyrano [3 ,4-d] isoxazolyl- 3-methyldimethylcarbamate A mixture of 5.0 g. (0.021 M) of8-chloro-4H[1]benzopyrano[3,4-d]isoxazolyl-methanol, 0.85 g. (0.021 M)of sodium hydride (as a 59% dispersion in oil) and 100ml. of dry benzeneis stirred for one hour and treated with a solution of 2.50 g. (0.021 M)of dimethylcarbamyl chloride in 50 ml. of benzene. After stirring at 70overnight, the mixture is extracted with two 50 m1. portions of waterand the organic phase dried over potassium carbonate. Removal of thesolvent leaves solids which are recrystallized from methanol to yield8-chloro-4H[l]benzopyrano [3,4-d]isoxazolyl-3-methy1 dimethylcarbamate,M.P. 131- 132".

Analysis.Calcd. for C H ClN O (percent): C, 54.46; H, 4.24; Cl, 11.48;N, 90.08. Found (percent): C, 54.60; H, 4.32; CI, 11.62; N, 9.10.

EXAMPLE l 8-chloro-4H-[1Jbenzopyrano[3,4-d1isoxazole- 3-carboxy1ate Whenpotassium 8-chloro-4H-[1]benzopyrano[3 ,4-d] isoxazole-3-carboxylate isstirred with dilute HCl a substance, M.P. 205, dec. is obtained. Aportion is insoluble in hot DMF While the remainder dissolves to give ayellow solution. The solid which is reisolated from the DMF by dilutionwith water is yellow and melts at 298-3 02. When the salt g.) is stirredwith ml. of trifluoroacetic acid on a steam bath,8-chloro-4H-[1]benzopyrano[3,4-d] isoxazole-S-carboxylate, M.P. 190-192"dec. is obtained.

EXAMPLE 1 l 8-chloro-4H- 1 benzopyrano 3,4-d] isoxazole-3-methano1 Asolution of 56.0 g. (0.2 mole) of 8-chloro-4H-[1]benzopyrano[3,4-d]isoxazole-3-carboxylate in 340 m1. of benzene is addeddropwise to a stirred mixture of 6.25 g. (0.164 mole) of LiAlI-I in 1000ml. of dry ether (from LiAlH while cooling in an ice bath. Afterstirring overnight and allowing the ice to melt, the mixture is againcooled and treated dropwise with 330 1111. of 3 N HCl. The mixture isstirred overnight and the solids insoluble in both layers filtered. Theether layer is separated, washed with Water and dried over K CO Theether is removed and the residue recrystallized from methanol to give 8-chloro 4H-[11benzopyrano[3,4-d]isoxazole-3-methanol, M.P. 158-160.

I claim: 1. A compound of the formula References Cited UNITED STATESPATENTS 3,553,229 1/1971 Freedman 260-307 NICHOLAS S. RIZZO, PrimaryExaminer R. V. RUSH, Assistant Examiner US. Cl. X.R.

